Pharmaceutical composition

ABSTRACT

The invention concerns pharmaceutical compositions containing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and solvates, crystalline forms and amorphous forms thereof, to the use of said compositions as a medicament; and to processes for the preparation of said compositions.

PHARMACEUTICAL COMPOSITION

This application is a continuation of U.S. patent application Ser. No.16/597,237, filed Oct. 9, 2019, which is a continuation of U.S. patentapplication Ser. No. 16/023,102, filed Jun. 29, 2018, which is acontinuation of U.S. patent application Ser. No. 15/348,053, filed Nov.10, 2016, which is a continuation of U.S. patent application Ser. No.14/884,343, filed Oct. 15, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/747,853, filed Jan. 23, 2013, which is acontinuation of U.S. patent application Ser. No. 13/293,368, filed Nov.10, 2011, which is a continuation of U.S. patent application Ser. No.12/411,865, filed Mar. 26, 2009, which claims the benefit under 35U.S.C. § 119(e) of U.S. Provisional Patent Application No. 61/040,372filed on Mar. 28, 2008. Each of the foregoing applications areincorporated herein by reference in their entirety.

The present invention relates to pharmaceutical compositions containinga hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (hereinafter referred to as the “Agent”),more particularly to orally deliverable compositions containing theAgent; to the use of said compositions as a medicament; and to processesfor the preparation of said compositions.

The Agent is disclosed in International Patent Application WO2007/076245 and is a potent inhibitor of MEK. The Agent is a hydrogensulphate salt of the compound with the structure of the Formula I.

The Agent possesses anti-proliferative activity and is expected to beuseful in the treatment of diseases or medical conditions mediated aloneor in part by MEK and particularly cancers such as brain, lung, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,ovarian, prostate, colorectal, oesophageal, testicular, gynecological orthyroid cancer or malignant melanoma. The Agent may also be used in thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)) and for the treatment ofother MEK mediated diseases, including pancreatitis or kidney disease(including proliferative glomerulonephritis and diabetes-induced renaldisease) or the treatment of pain in a mammal. The Agent is alsoexpected to be useful for the prevention of blastocyte implantation in amammal, or for treating a disease related to vasculogenesis orangiogenesis in a mammal. Such diseases may include tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

The free-base form of the Agent (i.e.6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide) has been classified as a BCS Class 4compound (according to the Biopharmaceutical Classification System asdefined by the Guidance for Industry: Waiver of In Vivo Bioavailabilityand Bioequivalence studies for immediate release solid oral dosage formsbased on a Biopharmaceutics Classification System) which indicates ithas a low solubility/dissolution rate and low permeability. Suchcompounds typically exhibit low and/or variable bioavailability andindeed the bioavailability of the free base form of the Agent from aconventional tablet formulation is relatively poor (˜18% in dogs).

The applicants have previously identified a particular salt form of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide, which shows unique pharmaceuticalproperties, making it particularly suitable for use in medicaments. Thisparticular salt form, namely the hydrogen sulphate salt (1:1 drug:H₂SO₄)of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide (hereinbefore and hereinafter referred toas the “Agent”), has been disclosed in WO 2007/076245. The salt iscrystalline and has surprisingly been found to possess improvedpharmaceutical properties when compared to the free-base form of theAgent and other salts of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide. In particular the dissolution rate ofthis salt as well as its bioavailability was found to be particularlyhigh when compared to the free base form of the Agent and other salts of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide.

In order to formulate a pharmaceutically active compound, such as theAgent, into a suitably acceptable dosage form, the active compoundshould, in addition to possessing acceptable biopharmaceuticalproperties, such as solubility and dissolution properties, also suitablypossess acceptable stability and handling properties. In this respect, aparticular problem occurs with the Agent. The free-base form of theAgent is a weakly basic compound and has two basic groups with pK_(a)'sof approximately 2.7 and 8.2. The pK_(a) value expresses the strength ofacids and base, i.e. the tendency for an acid to lose a proton or a baseto accept a proton (Bronsted J. N. Rec. trav. Chim. (47), 718, 1923).The Agent (i.e. hydrogen sulphate salt) is particularly liable todissociate into it's free-base form during formulation processing and/orstorage. Such conversion is undesirable because the free-base form ofthe Agent has poorer pharmaceutical properties, particularly in terms ofsolubility and dissolution rate.

Indeed such conversion should be avoided as it would be expected tocause a reduction in bioavailability and/or lead to an increase in interand intra-patient variability in plasma concentrations, both of whichcould lead to less than optimal treatment for patients.

There is, therefore, a need for pharmaceutical compositions containingthe Agent (i.e. hydrogen sulphate salt), particularly compositions inwhich stability of the Agent is maintained during processing and storageto ensure that acceptable absorption and/or bioavailability of the Agentis achieved upon dosing.

According to a first aspect of the present invention there is provided apharmaceutical composition comprising the Agent and a carrier matrix,wherein the carrier matrix consists essentially of one or morepharmaceutically acceptable carriers selected from the following:

(a) d-alpha-tocopheryl polyethylene glycol 1000 succinate;

(b) polyglycolised glycerides;

(c) polyethelylene glycols (PEGs); and

(d) hard fats;

and wherein the Agent is dispersed within the carrier matrix.

We have surprisingly found that stability of the Agent can be maintainedin the compositions of the present invention. Many of the materials thatare suitable for forming the carrier matrix are conventionally known inthe art as, for example, emulsifiers, solubilizers and absorptionenhancers and are used to improve the dissolution kinetics andbioavailability of poorly soluble drugs. However, the applicants havesurprisingly found that such excipients can also be used as inertcarrier matrices to stabilise the Agent in it's hydrogen sulphate formduring pharmaceutical processing and long-term storage.

Accordingly, the compositions of the present invention provide a meansof stabilising the Agent in it's hydrogen sulphate form duringformulation processing and subsequent long-term storage and as aconsequence ensure that acceptable absorption and/or bioavailability ofthe Agent is achieved upon dosing.

A further advantage of the present invention relates to themanufacturing process used to prepare suitable compositions of theinvention. While most conventional formulation processes, such as thoseused to formulate conventional tablet dosage forms, can involve a largenumber of time consuming and complex steps, possibly leading toinstability of the Agent, by comparison, the compositions of the presentinvention can be prepared by relatively simple and scalable processes.

The Carrier Matrix

The carrier matrix comprises one or more of the pharmaceuticallyacceptable carriers defined above. The carrier matrix may comprise asingle pharmaceutically acceptable carrier selected from the groupsdefined above, or alternatively, it may comprise a mixture. Thepharmaceutically acceptable carrier is selected from any one of thefollowing groups:

(a) d-alpha-tocopheryl polyethylene glycol 1000 succinate;

(b) polyglycolised glycerides;

(c) polyethelylene glycols; and

(d) hard fats.

D-alpha-tocopheryl polyethylene glycol 1000 succinate (otherwise knownas Vitamin E TPGS) is a water-soluble derivative of natural sourceVitamin E and has a dual nature, similar to an amphiphile, ofhydrophilicity and lipophilicty. Vitamin E TPGS is obtained byesterification of crystalline d-α-tocopheryl acid succinate bypolyethylene glycol (see U.S. Pharmacopeia 25—National Formulary 20).Vitamin E TPGS is already known for it's use in pharmaceuticalapplications as an emulsifier, solubilizer and absorption enhancer andWO 96/36316, U.S. Pat. No. 5,891,845 and WO 00/76482 may be cited asexamples. See also “Eastman Vitamin E TPGS” Eastman Brochure, EastmanChemical Co., Kingsport, Tenn. (November 2002) for further informationabout the use of Vitamin E TPGS in such applications.

Polyglycolysed glycerides are mixtures of glycerides of fatty acids andesters of polyoxyethylene with fatty acids. In these mixtures, the fattyacids are saturated or unsaturated and the glycerides are mono-, di- ortri-glycerides or mixtures thereof in any proportions. Examples ofsuitable polyglycolised glycerides include but are not limited tocaprylocaproyl macrogoglycerides (for example Labrasol), oleoylmacrogolglycerides (for example Labrafil M1944 CS), linoleoylmacrogolglycerides (for example Labrafil M2125 CS), lauroylmacrogolglycerides (for example Lauroyl Macrogol-32 Glycerides) andstearoyl macrogolglycerides for example Gelucire 50/13 (see PhEur 6^(th)Edition 2008 for further details of these polyglycolised glycerides). Ina particular group of compositions, the polyglycolised glyceridescontained in the carrier matrix have an hydrophilic-to-lipophillicbalance value (HLB) of greater than 10. In a further particular group ofcompositions, the polyglycolised glycerides contained in the carriermatrix are dispersible in water. In a further particular group ofcompositions, the polyglycolised glycerides are lauroylmacrogolglycerides or stearoyl macrogolglycerides. In yet a furtherparticular group of compositions, the polyglycolised glycerides arelauroyl macrogolglycerides. In yet a further particular group ofcompositions, the polyglycolised glyceride is Lauroyl Macrogol-32Glycerides or Gelucire 50/13. In yet a further particular group ofcompositions, the polyglycolised glyceride is Lauroyl Macrogol-32Glycerides. Lauroyl Macrogol-32 Glycerides (commercially supplied asGelucire 44/14 or Acconon® C-44, EP) is a saturated polyglycolizedglyceride consisting of mono-, di- and triglycerides and of mono- anddi-fatty acids of polyethylene glycol (PEG). Lauroyl Macrogol-32Glycerides is semi-solid/solid at room temperature, having a meltingpoint of 44° C. and is obtained from the reaction of hydrogenated palmkernel oil with polyethylene glycol 1500.

Polyethylene glycols USP (PEG), alternatively known as macrogols (seePhEur 6^(th) Edition 2008) are hydrophilic polymers of oxyethylene. PEGshaving an average molecular weight greater than 900 daltons aregenerally semi-solid or solid at ambient temperature. A suitable averagemolecular weight range for PEGs in the present invention is 900 to35,000 daltons. Suitable commercially available products include but arenot limited to PEG 900, PEG 1000, PEG 1450, PEG 2000, PEG 6000 and PEG20000. In a particular group of compositions, the PEG(s) present in thecarrier matrix have an average molecular weight range of between 900 and25,000 daltons. In a further particular group of formulations of thisembodiment, this PEG has an average molecular weight of around 6,000daltons. In yet a further particular group of formulations of thisembodiment, the PEG has an average molecular weight of around 20,000daltons.

Hard fats are solid mixtures of monoglycerides, diglycerides andtriglycerides, which are practically insoluble in water. Examples ofsuitable hard fats include but are not limited to Gelucire 33/01 (seeUSP-NF ‘Hard fat’), Gelucire 39/01 (see USP-NF and EP ‘Hard fat’) andGelucire 43/01 (see EP 3^(rd) edition and USP24/NF19 ‘Hard fat’).

According to one embodiment of the invention, the carrier matrixconsists of one or more pharmaceutically acceptable carriers selectedfrom the following:

(a) d-alpha-tocopheryl polyethylene glycol 1000 succinate;

(b) polyglycolised glycerides; and

(c) polyethelylene glycols (PEGs);

wherein the Agent is dispersed within the carrier matrix.

In a further embodiment of the invention, the carrier matrix is VitaminE TPGS.

In yet a further embodiment of the invention, the carrier matrix is apolyglycolized glyceride. Conveniently, the polyglycolized glyceride isLauroyl Macrogol-32 Glycerides or Gelucire 50/13, particularly LauroylMacrogol-32 Glycerides.

In a further embodiment of the invention, the carrier matrix comprises amixture of Vitamin E TPGS and at least one polyglycolised glyceride.Conveniently the at least one polyglycolised glyceride present in thisembodiment is Lauroyl Macrogol-32 Glycerides and suitably the LauroylMacrogol-32 Glycerides is present in an amount to make up 1-60% byweight of the carrier matrix component of the composition, andconveniently approximately 30-55%, and yet more convenientlyapproximately 50% by weight of the carrier matrix component of thecomposition. Preferably, Lauroyl Macrogol-32 Glycerides is the onlypolyglycolized glyceride present in this embodiment.

In a further embodiment of the invention, the carrier matrix comprises amixture of Vitamin E TPGS and at least one PEG. Conveniently the atleast one PEG present in this embodiment has an average molecular weightof between 900 and 25000 daltons and suitably the PEG is present in anamount to make up 1-30% by weight of the carrier matrix component of thecomposition, and conveniently approximately 5-15%, and yet moreconveniently approximately 10% by weight of the carrier matrix componentof the composition. Preferably, there is only one PEG present in thisembodiment. In a particular group of formulations of this embodiment,this PEG has an average molecular weight of 6000 daltons. In yet afurther particular group of formulations of this embodiment, the PEG hasan average molecular weight of 20000 daltons. In yet a furtherparticular group of formulations of this embodiment, the PEG has anaverage molecular weight of 1000 daltons.

It is to be understood that the term ‘approximately’ as used hereinaboveto refer to the proportion of excipients such as Lauroyl Macrogol-32Glycerides or PEG in the carrier matrix component of the compositionrefers to ±2% by weight of the carrier matrix component.

Suitably the composition contains from 40 to 99% by weight, particularlyfrom approximately 60 to 95% by weight, more particularly fromapproximately 65 to 95% by weight of the carrier matrix.

In a particular group of compositions of the present invention, thecomposition contains from approximately 90-95% by weight of the carriermatrix and more particularly approximately 95% by weight of the carriermatrix.

In a further particular group of compositions of the present invention,the composition contains from approximately 85-90% by weight of thecarrier matrix and more particularly approximately 90% by weight of thecarrier matrix.

In yet a further particular group of compositions of the presentinvention, the composition contains from approximately 75-85% by weightof the carrier matrix and more particularly approximately 80% by weightof the carrier matrix.

In yet a further particular group of compositions of the presentinvention, the composition contains from approximately 65-80% by weightof the carrier matrix and more particularly approximately 70% by weightof the carrier matrix.

It is to be understood that the term ‘approximately’ when relating tothe proportion of carrier matrix in the composition refers to ±2% byweight of the total composition. So by way of example, if thecomposition is said to contain approximately 70% by weight of thecarrier matrix, this would encompass compositions containing between68-72% by weight of carrier matrix.

In yet a further particular group of compositions of the presentinvention, the composition contains 79-81%, such as for example 79.83%,by weight of the carrier matrix.

The Agent

Typically the Agent will be present in an amount within the range offrom 1 to 50%, suitably from about 1 to 35% and especially from about 5to 30% by weight of the composition. In a particular group ofcompositions, the Agent will be present in an amount of about 5% byweight of the final composition. In a further particular group ofcompositions, the Agent will be present in an amount of about 10% byweight of the final composition. In yet a further particular group ofcompositions, the Agent will be present in an amount of about 20% byweight of the final composition. In yet a further particular group ofcompositions, the Agent will be present in an amount of about 30% byweight of the final composition. In yet a further particular group ofcompositions, the Agent will be present in an amount of 19-21%, such asfor example 20.17%, by weight of the final composition.

It is to be understood that the term ‘about’ when relating to theproportion of Agent present in the composition refers to +2% by weightof the total composition.

Suitably a unit dose of the composition according to the invention maycontain from 0.01 mg to 500 mg of Agent. Suitably each therapeutic doseof the composition will contain a sufficient quantity of the Agent toprovide a daily dose of the Agent in one or more units. Suitablequantities of the Agent in unit doses in different embodiments include,for example approximately 6.05, 12.1, 18.15, 30.25, 60.5, 72.6, 78.65,84.7, 90.75, 96.8, 102.85, 108.9, 114.95, 121, 151.25, 181.5, 242,302.5, 363, 423.5, 484 mg or higher depending upon the dose required andthe particular form of the pharmaceutical composition. In a particularembodiment a unit dose of the composition contains from 1 mg to 150 mgof Agent and particularly from 50 mg to 130 mg of Agent, such as forexample approximately 72.6, 78.65, 84.7, 90.75, 96.8, 102.85, 108.9,114.95 or 121 mg of the Agent, and especially 72.6, 78.65, 84.7, 90.75or 96.8 mg of the Agent. The term ‘approximately’ as used directlyhereinabove is defined as +/−2 mg of the weight quantity specified. In aparticular embodiment a unit dose of the composition contains 90.75 or60.5 mg of the Agent. In a particular embodiment a unit dose of thecomposition contains 90.75 mg of the Agent. In a particular embodiment aunit dose of the composition contains 60.5 mg of the Agent.

The Agent may be used in various forms, all of which are included withinthe scope of the invention. These include amorphous or crystallineforms, and anhydrous forms as well as solvates or hydrates. In aparticular group of formulations, the Agent is crystalline and is in theanhydrous form.

We have found that the Agent can be stabilised in a suitable carriermatrix of the present invention. As used herein, the term “stabilised”means that the active ingredient(6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide) present in the composition followingprocessing and/or storage is substantially present as the hydrogensulphate salt, i.e. as the Agent as opposed to the free base form of theAgent. The skilled person would readily appreciate that an indication ofthe amount of the free base form of the Agent and the amount of theAgent (i.e. hydrogen sulphate form) in a composition can be obtainedusing techniques such as for example XRPD and ¹⁹F Solid State NMRSpectroscopy and can also be monitored by dissolution testing.

As used herein, the term “dispersed” describes a two-phase system whereone phase consists of the Agent distributed in a second phase whichcomprises a carrier matrix, the Agent being the dispersed phase and thecarrier matrix comprising phase being the continuous phase. In aparticular group of formulations, the Agent forming the “dispersedphase” is in the form of finely divided particles that are distributedthroughout the “second phase” comprising the carrier matrix. In aparticular group of formulations, greater than 60% by weight of thetotal amount of the Agent present in the composition is dispersed. Inyet a particular group of formulations, greater than 90% and preferablygreater than 95% by weight of the total amount of the Agent present inthe composition is dispersed. The skilled person would appreciate thatan indication of the proportion of drug present in the form of a soliddispersion can be ascertained by the use of techniques such asdifferential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis(TGA), Differential Scanning Microcalorimetry and ¹⁹F Solid State NMRSpectroscopy. The skilled person would also appreciate that thecrystallinity of the drug in the formulation can be determined usingtechniques such as, for example, by X-ray diffraction.

In a particular group of compositions of the present invention, theparticle size of the dispersed Agent may vary from about 1 to 20 micron.Preferably the dispersed Agent has a particle size distribution suchthat 90% of the particles have a diameter of less than 15 microns.

In one embodiment of the invention, the Agent is dispersed within thecarrier matrix and no additional solvents or additives are present.Compositions of this embodiment can be prepared with a particularly highloading of the Agent and this is advantageous because additionalcomponents often introduce drawbacks, such as a potentially increasedtoxicity risk and an increased size of the dosage form, both of whichcan contribute to poor patient compliance and acceptability of thetreatment.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising:

(i) the Agent; and

(ii) a carrier matrix;

wherein the carrier matrix has any of the meanings defined hereinbefore;and wherein the Agent is dispersed within the carrier matrix and thecomposition is semi-solid or solid at ambient temperature.

As used herein, the term “semi-solid” describes a component orcomposition, which has a rigidity and viscosity intermediate between asolid and a liquid. A semi-solid does not flow as a powder and is notliquid at ambient temperature (i.e. it has a melting point above ambienttemperature). As used herein, the term “solidify” means to form a solidor semi-solid. Ambient temperature is to be understood as meaning atemperature in the range of 18 to 23° C.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising:

(i) the Agent; and

(ii) a carrier matrix consisting essentially of Vitamin E TPGS;

wherein the Agent is dispersed within the Vitamin E TPGS and thecomposition is semi-solid or solid at ambient temperature.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising:

(i) the Agent; and

(ii) a carrier matrix consisting essentially of a polyglycolizedglyceride;

wherein the Agent is dispersed within the polyglycolized glyceride andthe composition is semi-solid or solid at ambient temperature.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising:

(i) the Agent; and

(ii) a carrier matrix consisting essentially of Vitamin E TPGS andLauroyl Macrogol-32 Glycerides;

wherein the Agent is dispersed within the carrier matrix and thecomposition is semi-solid or solid at ambient temperature.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising:

(i) the Agent; and

(ii) a carrier matrix consisting essentially of Vitamin E TPGS and PEG;

wherein the Agent is dispersed within the carrier matrix and thecomposition is semi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 15 to 30 (particularly from 15 to 25) parts of the Agent; and

(ii) from 70 to 85 (particularly from 75 to 85) parts of a carriermatrix;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100,the carrier matrix has any of the meanings defined hereinbefore and theAgent is dispersed within the carrier matrix and the composition issemi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 15 to 25 (particularly from 18 to 22) parts of the Agent; and

(ii) from 75 to 85 (particularly from 78 to 82) parts of a carriermatrix;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100,the carrier matrix has any of the meanings defined hereinbefore and theAgent is dispersed within the carrier matrix and the composition issemi-solid or solid at ambient temperature.

In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 25 to 40 (particularly from 25 to 35) parts of the Agent; and

(ii) from 60 to 75 (particularly from 65 to 75) parts of a carriermatrix;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100,the carrier matrix has any of the meanings defined hereinbefore and theAgent is dispersed within the carrier matrix and the composition issemi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 25 to 35 (particularly from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (particularly from 68 to 72) parts of a carriermatrix;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100,the carrier matrix has any of the meanings defined hereinbefore and theAgent is dispersed within the carrier matrix and the composition issemi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 15 to 25 (particularly from 18 to 22) parts of the Agent; and

(ii) from 75 to 85 (particularly from 78 to 82) parts of Vitamin E TPGS;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100;and wherein the Agent is dispersed within the Vitamin E TPGS and thecomposition is semi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 25 to 35 (particularly from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (particularly from 68 to 72) parts of Vitamin E TPGS;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100;and wherein the Agent is dispersed within the Vitamin E TPGS and thecomposition is semi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) 19-21, such as for example 20.17, parts of the Agent; and

(ii) 79-81, such as for example 79.83, parts of Vitamin E TPGS;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100;and wherein the Agent is dispersed within the Vitamin E TPGS and thecomposition is semi-solid or solid at ambient temperature.In a particular embodiment there is provided a pharmaceuticalcomposition comprising:

(i) from 25 to 35 (particularly from 28 to 32) parts of the Agent; and

(ii) from 65 to 75 (particularly from 68 to 72) parts of a carriermatrix comprised of a mixture of Vitamin E TPGS and at least onepolyglycolized glyceride;

wherein both parts are by weight and the sum of the parts (i)+(ii)=100;and wherein the Agent is dispersed within the Vitamin E TPGS and atleast one polyglycolized glyceride and the composition is semi-solid orsolid at ambient temperature.

The Formulation

Optionally, additional excipients may be included in the compositionaccording to the present invention providing that inclusion of suchexcipients does not unacceptably impact the stability of the salt-formof the Agent within the composition. Accordingly, one skilled in the artwould appreciate that in certain embodiments of the invention, the Agentpresent in a composition of the invention could be dispersed in amixture made up of the carrier matrix and additional excipients, such asis described in some of the particular Examples that follow hereinafter.Additional excipients, which may be present include for examplepreservatives, stabilisers, emulsifiers, anti-oxidants, sweeteners,flavouring agents, pH adjusting agents, dispersion aids (for examplesurfactants, such as for example ethoxylated castor oil (Cremophor EL),ethoxylated hydrogenated castor oil (Cremophor RH40) or polysorbate 80)and viscosity modifiers. Such additional excipients are well known tothose skilled in the art and are described in, for example the Handbookof Pharmaceutical Excipients, 4^(th) Edition, American PharmaceuticalAssociation; The Theory and Practice of Industrial Pharmacy, 3^(rd)Edition, Lachman et al. 1986; Pharmaceutical Dosage Forms: TabletsVolume 1, 2^(nd) Edition, Lieberman, Hebert A., et al, 1989; ModernPharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 3^(rd)edition, 1995; and Remington's Pharmaceutical Sciences, 20^(th) Edition,2000.

Suitably the composition according to the present invention is in a formadapted for oral administration, for example a capsule formulation or aliquid dispersion suitable for oral administration. Suitable capsuleformulations are well known and include for example solid, liquid orsemi-solid compositions contained within soft or hard gelatin capsules;water-soluble cellulose ether (for example hypromellose) or starchcapsules.

Accordingly, a further aspect of the invention is a pharmaceuticalcomposition adapted for oral administration comprising the Agent and acarrier matrix, wherein the carrier matrix has any of the meaningsdefined hereinbefore; and wherein the Agent is dispersed within thecarrier matrix.

A yet further aspect of the invention is a pharmaceutical capsulecomposition comprising the Agent and a carrier matrix, wherein thecarrier matrix has any of the meanings defined hereinbefore; and whereinthe Agent is dispersed within the carrier matrix.

The compositions according to the present invention may be preparedusing conventional methods well known in the pharmaceutical art. Forexample in one particular embodiment, the component(s) of the carriermatrix are heated until molten and the Agent, which may have been sizereduced for example by milling or micronization, is graduallyincorporated to the molten mixture with constant agitation/stirring toensure homogenous distribution. The molten mixture can then be filledinto hard or soft capsules and allowed to cool and form a viscousliquid, solid or semi-solid mass within the capsule. The body and cap ofthe capsule can be sealed by conventional methods known in the art, suchas for example banding.

Alternatively, compositions of the invention may be prepared by otherconventional methods such as for example, melt extrusion or meltgranulation (see A. Royce, J, Drug Dev. Ind. Pharm. 22 (1996) 917-924,G. Verreck, Bull. tech. Gattefossé (2004) 85-95 and J. Breitenbach, Eur.J. Pharm. Biopharm. 54 (2002) 107-117 for details of suitablemanufacturing methods).

The Agent possesses anti-proliferative activity and accordingly thecompositions according to the present invention are useful in thetreatment of conditions such as those described in International PatentApplication WO 2007/076245, which discloses the Agent (i.e. hydrogensulphate salt) and also in WO 03/077914, in which the free base form ofthe Agent is exemplified. For example, the composition of the inventionis useful for the treatment of many common human cancers such asmalignant melanoma, brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, esophageal, testicular, gynecological or thyroid cancer. Itis further expected that the compositions of the invention will beuseful for the treatment of other diseases involving excessive cellularproliferation such as benign skin hyperplasia, for example psoriasis,restenosis or benign prostatic hypertrophy (BPH). Other examples of MEKmediated diseases, which may also be treated using the Agent includepancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal. Furthermore, the Agent may also be used for theprevention of blastocyte implantation in a mammal, or for treating adisease related to vasculogenesis or angiogenesis in a mammal. Suchdiseases may include tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, excema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

A further aspect of the present invention provides a pharmaceuticalcomposition according to the invention as hereinbefore defined for useas a medicament.

The Agent present in the compositions of the invention possessesanti-proliferative properties such as anti-cancer properties, which arebelieved to arise from its MEK inhibitory activity. Accordingly thecomposition of the invention is expected to be useful in the treatmentof diseases or medical conditions mediated alone or in part by MEK, i.e.the composition of the invention may be used to produce a MEK inhibitoryeffect in a warm-blooded animal in need of such treatment. Thus thecomposition of the invention provides a method for treating theproliferation of malignant cells characterised by inhibition of MEK,i.e. the composition of the invention may be used to produce ananti-proliferative effect mediated alone or in part by the inhibition ofMEK. Accordingly the composition of the invention is expected to beuseful in the treatment of cancer by providing an anti-proliferativeeffect, particularly in the treatment of MEK sensitive cancers such asthe cancers hereinbefore described.

In an embodiment of the invention there is provided, a pharmaceuticalcomposition according to the invention as hereinbefore defined for usein producing an anti-proliferative effect in a warm-blooded animal(preferably a human). In another embodiment there is provided apharmaceutical composition according to the invention as hereinbeforedefined for use in the treatment of a cancer. In a still furtherembodiment there is provided a pharmaceutical composition according tothe invention for use in the prevention or treatment of tumours, whichare sensitive to the inhibition of MEK.

A further aspect of the present invention provides the use of acomposition according to the invention as hereinbefore defined in themanufacture of a medicament for use in producing an anti-proliferativeeffect in a warm-blooded animal (preferably a human).

A further aspect of the present invention provides the use of acomposition according to the invention as hereinbefore defined in themanufacture of a medicament for use in the treatment of a cancer.

A further aspect of the present invention provides a method forpreventing an unacceptable reduction in bioavailability of the Agent ina patient in need of the Agent comprising orally administering to saidpatient a pharmaceutical composition according to the present inventionas hereinbefore defined.

A further aspect of the present invention provides the use of apharmaceutical composition according to the present invention ashereinbefore defined in the manufacture of a medicament for preventingan unacceptable reduction in bioavailability of the Agent.

Pharmaceutical compositions of the present invention may be administeredalone as a sole therapy or can be administered in addition with one ormore other substances and/or treatments. Such conjoint treatment may beachieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to compositions of the present invention may be: surgery,radiotherapy or chemotherapy. Such chemotherapy may cover categories oftherapeutic agent such as: (i) other antiangiogenic agents such as thosewhich inhibit the effects of vascular endothelial growth factor, (forexample the anti-vascular endothelial cell growth factor antibodybevacizumab [Avastin™], and those that work by different mechanisms fromthose defined hereinbefore (for example linomide, inhibitors of integrinαvβ function, angiostatin, razoxin, thalidomide, MMP-2(matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase9) inhibitors, and COX-II (cyclooxygenase II) inhibitors), and includingvascular targeting agents (for example combretastatin phosphate andcompounds disclosed in International Patent Applications WO 00/40529, WO00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 and the vasculardamaging agents described in International Patent ApplicationPublication No. WO 99/02166 the entire disclosure of which document isincorporated herein by reference, (for exampleN-acetylcolchinol-O-phosphate));

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example anastrozole,letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (forexample flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRHagonists and antagonists (for example goserelin acetate, luprolide,buserelin), inhibitors of 5α-reductase (for example finasteride),anti-invasion agents (for example metalloproteinase inhibitors likemarimastat and inhibitors of urokinase plasminogen activator receptorfunction) and inhibitors of growth factor function, (such growth factorsinclude for example platelet derived growth factor and hepatocyte growthfactor), such inhibitors include growth factor antibodies, growth factorreceptor antibodies, (for example the anti-erbb2 antibody trastuzumab[Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors for exampleinhibitors of the epidermal growth factor family (for example EGFRfamily tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)) and serine/threonine kinase inhibitors); and

(iii) antiproliferative/antineoplastic drugs and combinations thereof,as used in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,tegafur, purine and adenosine analogues, cytosine arabinoside);antitumour antibiotics (for example anthracyclines like adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin and idarubicin,mitomycin-C, dactinomycin, mithramycin); platinum derivatives (forexample cisplatin, carboplatin); alkylating agents (for example nitrogenmustard, melphalan, chlorambucil, busulphan, cyclophosphamide,ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for examplevinca alkaloids like vincristine, vinblastine, vindesine, vinorelbine,and taxoids like taxol, taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan,camptothecin and also irinotecan); also enzymes (for exampleasparaginase); and thymidylate synthase inhibitors (for exampleraltitrexed);

and additional types of chemotherapeutic agent include:

(iv) biological response modifiers (for example interferon);

(v) antibodies (for example edrecolomab);

(vi) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(vii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(viii) immunotherapy approaches, including for example ex-vivo and invivo approaches to increase the immunogenicity of patient tumour cells,such as transfection with cytokines such as interleukin 2, interleukin 4or granulocyte-macrophage colony stimulating factor, approaches todecrease T-cell anergy, approaches using transfected immune cells suchas cytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

(ix) mitotic inhibitors, for example vinblastine;

(x) alkylating agents, for example cis-platin, carboplatin andcyclophosphaniide;

(xi) anti-metabolites, for example 5-fluorouracil, cytosine arabinsideand hydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent EP 0239362 B1 (issued Apr. 12, 1991) suchasN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino-2-thenoyl)-L-glutamicacid;

(xii) growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for example,interferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

In particular, pharmaceutical compositions of the invention are used inconjunction with an effective amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents.

In a particular embodiment, anti-angiogenesis agents, such as MMP-2(matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used inconjunction with a pharmaceutical composition of the present invention.Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib),valdecoxib, and rofecoxib. Examples of useful matrix metalloprotienaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Publication EP0818442A2 (published Jan. 14, 1998), European Patent EP 1004578 B1(issued Feb. 25, 2004), WO 98/07697 (published Feb. 26, 1998), WO98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (publishedAug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931,788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. WO 99/07675 (published Feb. 18, 1999),European Patent EP0952148 B1 (issued May 12, 2004), Great Britain PatentApplication No. 9912961.1 (filed Jun. 3, 1999), U.S. ProvisionalApplication No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan.19, 1999), and European Patent Publication 780,386 (published Jun. 25,1997.), all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The dose of Agent required in the composition of the invention for thetherapeutic or prophylactic treatment of a particular disease or medicalcondition (for example a proliferative disease) will necessarily bevaried depending on for example, the host treated and the severity ofthe illness being treated. The amount of the active compoundadministered will be dependent on the subject being treated, theseverity of the disorder or condition, the rate of administration, thedisposition of the compound and the discretion of the prescribingphysician. However, an effective dosage is in the range of about 0.01 toabout 100 mg per kg body weight per day, preferably about 1 to about 35mg/kg/day, in single or divided doses. For a 70 kg human, this wouldamount to about 0.7 to 7000 mg/day, preferably about 70 to about 2500mg/day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day. A unit dose of thecomposition will usually contain, for example 1-500 mg of activeingredient, and preferably 5-150 mg of active ingredient. Preferably adaily dose in the range of 0.03-6 mg/kg is envisaged.

The invention is illustrated below by the following non-limitingexamples, wherein unless stated otherwise, the “Agent” is a hydrogensulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows X-ray powder diffraction data for compositions containingvarying amounts of the free-base form of the Agent and the Agent (i.e.hydrogen sulphate salt), where the x-axis shows 2-Theta values and they-axis shows Lin (Counts). The data provides an indication of the levelof detection of free-base form of the Agent in a composition using X-raypowder diffraction.

FIG. 2 shows X-ray powder diffraction patterns for compositions of thepresent invention following manufacture, where the x-axis shows 2-Thetavalues and the y-axis shows Lin (Counts). The data demonstrates thatonly the Agent (i.e. hydrogen sulphate form) is detectable in thecompositions.

FIG. 3 shows ¹⁹F SS-NMR spectra used to determine the approximate limitof detection of free-base form of the Agent in a Vitamin E TPGScomposition using ¹⁹F SS-NMR.

FIG. 4 shows ¹⁹F SS-NMR spectra of the composition of Example 1.2. Thespectra demonstrates the absence of a detectable level of free-base formof the Agent in the composition.

FIG. 5 shows ¹⁹F SS-NMR spectra of the composition of Example 1.3. Thespectra demonstrates the absence of a detectable level of free-base formof the Agent in the composition.

EXAMPLE 1: PREPARATION OF COMPOSITIONS OF THE PRESENT INVENTION

The compositions shown in Table 1 were prepared by heating the carriermatrix to a temperature of between 60 to 70° C. with the aid of an oven.The temperature was held for approximately 2 hours to ensure that allthe material is fully molten. The Agent was then gradually added andmechanically stirred into the carrier matrix using a magnetic stir baror high-shear homogeniser. The system was maintained at a sufficientlyhigh temperature to keep the mixture in a molten state during thestirring, which was continued until a visibly homogenous mixture wasobtained. Stirring times varied depending on the particular compositionbut generally were in the range of 3 to 35 minutes. The resultantmixture was then filled into HPMC capsules and allowed to cool toambient temperature. Capsules were sealed and generally stored underrefrigerated conditions until use.

TABLE 1 Agent Carrier Matrix Example (mg per capsule) (mg per capsule)1.1 12.10 mg Vitamin E TPGS 107.90 mg 1.2 30.25 mg Vitamin E TPGS 119.75mg 1.3  6.05 mg Vitamin E TPGS 113.95 mg 1.4 60.36 mg Vitamin E TPGS(71.06 mg) Gelucire 44/14 (71.49 mg) 1.5 30.25 mg Vitamin E TPGS (107.78mg) PEG 20000 (11.98 mg) 1.6 30.25 mg Vitamin E TPGS (107.78 mg) PEG6000 (11.98 mg) 1.7 30.25 mg Gelucire 44/14 119.75 mg

EXAMPLE 2: STABILITY OF COMPOSITIONS OF THE PRESENT INVENTION BY X-RAYPOWDER DIFFRACTION (XRPD)

An indication of the stability of the Agent (i.e. hydrogen sulphatesalt) in a formulation can be provided by XRPD. This technique iscapable of simultaneously detecting the crystalline free-base form ofthe Agent and the crystalline hydrogen sulphate salt form of the Agentwithin the composition. Samples of the compositions were mounted onsilicon wafer mounts and analysed using the Siemen's D5000 X-raydiffractometer. The samples were exposed for 4 seconds per 0.02° θ overthe range 2° to 40° 2θ in continuous scan, theta-theta mode.

The approximate limit of detection of the crystalline free-base form ofthe Agent within a composition of the invention was determined bypreparing formulations with varying relative amounts of the crystallinefree-base form of the Agent to the crystalline Agent (i.e. hydrogensulphate salt-form) and these compositions were analysed by XRPD. FIG. 1shows that the free-base form of the Agent was detectable to a level of2.5% w/w free-base in a Vitamin E TPGS based composition which alsonominally contained 21.2% w/w of the Agent.

XRPD patterns were obtained for each of the compositions described inExamples 1.1, 1.2 and 1.3 immediately after their manufacture. Thesepatterns (shown in FIG. 2) demonstrate only the presence of the Agent(i.e. hydrogen sulphate form).

EXAMPLE 3: STABILITY OF COMPOSITIONS OF THE PRESENT INVENTION BY SOLIDSTATE NMR SPECTROSCOPY

An indication of the stability of the Agent in compositions of theinvention can be provided by using ¹⁹F Solid State NMR Spectroscopy (¹⁹FSS-NMR). This technique is capable of detecting both the crystallinefree-base form of the Agent and the crystalline Agent (i.e. hydrogensulphate salt form) within the composition. The free-base form of theAgent and the Agent (i.e. hydrogen sulphate salt) give distinct andcharacteristic fluorine peaks in the spectrum. These peaks can beintegrated in the normal manner for NMR signals and the ratio of thepeaks is proportional to the ratio of the two solid state forms present,i.e. the free-base form of the Agent and the Agent (i.e. hydrogensulphate form). Analysis of compositions was carried out by placingsample material in a 4 mm MAS (Magic Angle Spinning) rotor. ¹⁹F NMR [376MHZ] spectra with ¹H composite pulse decoupling [TPPM15] was recorded onthe Avance 400 spectrometer using the 4 mm HFX (Bruker Biospin) probe.All samples were spun at 12 kHz using the pulse program “aringdec”(anti-ring with decoupling). It should be noted that the frictionalforces associated with the technique of magic angle spinning couldresult in sample heating, up to approximately 10° C.-20° C. aboveambient temperature.

The approximate limit of detection of the crystalline free-base form ofthe Agent within a composition of the invention was determined bypreparing formulations with varying relative amounts of the crystallinefree-base form of the Agent and the crystalline Agent (i.e. hydrogensulphate salt-form). These formulations were then analysed by ¹⁹FSS-NMR. The NMR spectra depicted in FIG. 3 show that the free-base formof the Agent was detectable to a level of 1% w/w free-base in a VitaminE TPGS based composition that also contained 28.9% w/w of the Agent(i.e. hydrogen sulphate salt).

Formulations described in Examples 1.2 and 1.3 were tested by ¹⁹F SS-NMRpost manufacture and no evidence of the presence of free-base form ofthe Agent was found, see FIG. 4 and FIG. 5. Some sample heating wasobserved with the analysis of these samples, which may have led to theappearance of an isotropic peak at −129.5 ppm. Without wishing to bebound by any particular theory, the peak may be attributed to thepresence of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide dissolved in Vitamin E TPGS, which hasbecome molten upon sample heating.

EXAMPLE 4. STABILITY OF COMPOSITIONS ON STORAGE

Stability studies on the compositions described in Examples 1.2 and 1.3for up to 12 months have shown that they are stable at elevatedtemperatures and high humidities whilst being enclosed in whitehigh-density polyethylene (HDPE) bottles (induction sealed andcontaining desiccant). No significant changes in the stability data forthe compositions of Example 1.2 and 1.3 were observed after 12 monthsstorage in the HDPE bottles at 25° C./60% Relative Humidity (RH) and 30°C./65% RH, see data in Table 1 and Table 2.

TABLE 1 Composition from Example 1.3 stored in induction sealed HDPEbottles containing desiccant at 25° C./60% RH and 30° C./65% RH 12months 12 months Test Initial 25° C./60% RH 30° C./65% RH DescriptionPlain, white, No change No change banded capsules Drug Content^(a)  4.9 4.8  4.8 Total organic impurities^(b)  0.64 (4)  0.68 (4)  0.67 (5) byHPLC (% area) Dissolution Complies Complies with Complies with with USPUSP USP Mean at 45 minutes (%) 107 96 99 RSD at 45 minutes (%)  3.6  4.0 2.4 Water content (% w/w)  1.2  0.4  0.4 Polymorphic identity by Nofree-base No free-base No free-base XRPD form of form form the Agent ofthe Agent of the Agent detected detected detected ^(a)Expressed as mgFree Base equivalent. Analysed using gradient reversed phase liquidchromatography with UV detection, using YMC-Pack ODS-AQ, 3 μm, 150 × 4.6mm (id) column, Sample diluent 10% TH, 90% Methanol. Mobile Phase A:0.01% HFBA/1% IPA/Water (v/v/v), Mobile Phase B: 0.01% HFBA/1% IPA/ACN(v/v/v). Gradient: 0 mins = 30% B, 7.5 min = 30% B, 10.5 min = 36% B,16.5 min = 36% B, 30.5 min = 90% B, 33 min = 90% B, 34 min = 30% B, 40min = 30% B. HPLC parameters: Flow rate = 1.2 ml/min, Column temperature= 40° C., Wavelength = 258 nm, Injection volume = 10 μl. ^(b)Totalorganic impurities includes organic impurities at ≥0.05. The numbers inparentheses refer to the number of organic impurities detected at≥0.05%.

TABLE 2 Composition from Example 1.2 stored in induction sealed HDPEbottles containing desiccant at 25° C./60% RH and 30° C./65% RH 12months 12 months 25° C./ 30° C./ Test Initial 60% RH 65% RH DescriptionPlain, white, No change No change banded capsules Drug contenta  24.724.5 24.6 Total organic impuritiesb  0.66 (4)  0.74 (6)  0.72 (6) byHPLC (% area) Dissolution Complies with Complies with Complies with USPUSP USP Mean at 45 minutes (%) 103 97 98 RSD at 45 minutes (%)  2.1  3.6 4.9 Water content (% w/w)  1.0  0.3  0.3 Polymorphic identity by Nofree-base No free-base No free-base XRPD form of form form the Agent ofthe Agent of the Agent detected detected detected ^(a)Expressed as mgFree Base equivalent. Analysed using gradient reversed phase liquidchromatography with UV detection, using YMC-Pack ODS-AQ, 3 μm, 150 × 4.6mm (id) column, Sample diluent 10% TH, 90% Methanol. Mobile Phase A:0.01% HFBA/1% IPA/Water (v/v/v), Mobile Phase B: 0.01% HFBA/1% IPA/ACN(v/v/v). Gradient: 0 mins = 30% B, 7.5 min = 30% B, 10.5 min = 36% B,16.5 min = 36% B, 30.5 min = 90% B, 33 min = 90% B, 34 min = 30% B, 40min = 30% B. HPLC parameters: Flow rate = 1.2 ml/min, Column temperature= 40° C., Wavelength = 258 nm, Injection volume = 10 μl. ^(b)Totalorganic impurities includes organic impurities at ≥0.05. The numbers inparentheses refer to the number of organic impurities detected at≥0.05%.

EXAMPLE 5. DISSOLUTION OF COMPOSITIONS OF THE PRESENT INVENTION

An in-vitro dissolution method was developed to test the performance offormulations contained within HPMC capsules. Dissolution in duplicate ortriplicate was carried out on the formulations listed below in Table 3.

Dissolution of capsules is performed according to the general procedureof the United States Pharmacopoeia Apparatus II (paddle). Samples of thedissolution medium are withdrawn at various time points after capsuleaddition and the6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide concentration is quantified by comparisonof its HPLC response peak area to that of a standard solution preparedat a level equivalent to 100% release of the compound. The method usesclear glass peak vessel dissolution pots, and Spiral Stainless SteelCapsule Sinkers are used to hold the capsules. 900 ml pH2.0 735 mOsmol\Lphosphate buffer solution is used at 27° C. and a paddle speed of 100rpm is used.

TABLE 3 Dissolution results Dissolution Dissolution at 50 at 50Formulation of minutes (%) Formulation of minutes (%) Example 1.1 100Comparator 1 73 (45 min) (2% w/w Free Base, 21.9% w/w Agent (i.e.hydrogen sulphate salt)) Example 1.2 99 Comparator 2 56 (40 min) (5% w/wFree Base, 18.2% w/w Agent (i.e. hydrogen sulphate salt)) Example 1.3 99Comparator 3 41 (batch 1) (20% w/w Free Base) Example 1.3 95 (batch 2)Example 1.5 96 Example 1.6 101 Example 1.7 95

In addition to the compositions described in Examples 1.1-1.3 and1.5-1.7, some further comparator formulations were manufactured usingmixtures of crystalline free-base and crystalline Agent (i.e. hydrogensulphate salt). The mixture of the two forms were dispersed in Vitamin ETPGS according to analogous methods to those described in Example 1 andfilled into HPMC capsules.

The dissolution data for the comparator formulations show thatdissolution decreased as the amount of free base form of the Agent inthe composition increased. A 17% drop in dissolution at 50 minutes isobserved for a formulation containing 2% w/w Free Base form of theAgent. The data generated by analysing the free-base containingcomparator formulations show that the dissolution method gives anindication of the level of free-base form of the Agent present withinthe compositions. The dissolution results for the compositions describedin Examples 1.1-1.3 and 1.5-1.7 show that 95% or greater dissolution isachieved indicating that the compound is substantially present in it'shydrogen sulphate salt-form (i.e. as the Agent).

EXAMPLE 6: PREPARATION OF FURTHER COMPOSITIONS OF THE PRESENT INVENTION

The compositions shown in Table 4 were prepared by heating the carriermatrix in an oven set at 70° C. for at least one hour. The Agent wasthen gradually added and mechanically stirred into the carrier matrixusing a magnetic stir bar or a high-shear homogeniser. The system wasmaintained at sufficiently high temperature to keep the mixture in amolten state during stirring. Stirring was performed until a visiblyhomogenous mixture was obtained. The time taken for this to be achievedvaried depending on the composition but was at least 10 minutes andcould have been up to 60 minutes. The systems ranged in total weightfrom 3.75 g to 75 g (as indicated in Table 4). The resultant mixture wasfilled into HPMC capsules and allowed to cool to ambient temperature andsolidify. Capsules were stored at either room temperature or underrefrigerated conditions until use.

TABLE 4 Agent Total weight (mg per Carrier Matrix of batch Examplecapsule) (mg per capsule) prepared (g) 6.1 30.25 mg Vitamin E TPGS(89.75 mg) 3.75 Tween 80 (30.00 mg) 6.2 30.25 mg Vitamin E TPGS (89.75mg) 3.75 Cremophor EL (30.00 mg) 6.3 30.25 mg Vitamin E TPGS (89.75 mg)3.75 Pluronic F-68 (30.00 mg) 6.4 30.25 mg Vitamin E TPGS (89.75 mg)3.75 PEG 1000 (30.00 mg) 6.5 30.25 mg Vitamin E TPGS (97.25 mg) 3.75 PEG1000 (22.50 mg) 6.6 30.25 mg Vitamin E TPGS (104.75 mg) 3.75 PEG 1000(15.00 mg) 6.7 30.25 mg Vitamin E TPGS (112.25 mg) 3.75 PEG 1000 (7.50mg) 6.8 30.25 mg Vitamin E TPGS (119.75 mg) 3.75 (API batch 1) 6.9 30.25mg Vitamin E TPGS (119.75 mg) 3.75 (API batch 2) 6.10 30.25 mg Vitamin ETPGS (119.75 mg) 3.75 (API batch 3) 6.11 30.25 mg Vitamin E TPGS (269.75mg) 7.5 6.12 30.25 mg Vitamin E TPGS (119.75 mg) 75 6.13 15.12 mgVitamin E TPGS (134.88 mg) 75 6.14  60.5 mg Vitamin E TPGS (239.5 mg) 156.15 90.75 mg Vitamin E TPGS (359.25 mg) 15

EXAMPLE 7. DISSOLUTION OF COMPOSITIONS IN PH 6.5 DISSOLUTION MEDIA

An in-vitro dissolution method employing pH 6.5 dissolution media wasused to test the performance of compositions contained within HPMCcapsules. The pH 6.5 dissolution method provided improved discriminationof the presence of free base form of the Agent in compositions whencompared with the dissolution method described in Example 5. Dissolutionin duplicate or triplicate was carried out on the formulations listed inTable 4 and also on the formulation of Example 1.7.

Dissolution of capsules was performed according to the general procedureof the United States Pharmacopoeia Apparatus II (paddle). Samples of thedissolution medium are withdrawn at various time points after capsuleaddition and the6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide concentration is quantified by comparisonof its HPLC response peak area to that of a standard solution preparedat a level equivalent to 100% release of the compound. The method usesclear glass peak vessel dissolution pots, and Spiral Stainless SteelCapsule Sinkers are used to hold the capsules. 1000 ml of pH 6.5dissolution media is used at 37° C. and a paddle speed of 50 rpm isused.

The pH 6.5 dissolution media is prepared by the addition of 1.74 gsodium hydroxide pellets, 19.77 g sodium dihydrogenphosphate hydrous (or17.19 g sodium dihydrogenphosphate anhydrous) and 30.93 g sodiumchloride to 5 litres of deionised water. The pH is then adjusted to 6.5with 1M hydrochloric acid or 1M sodium hydroxide.

In addition to the compositions described in Table 4, some furthercomparator formulations were manufactured using mixtures of crystallinefree-base of the Agent and crystalline Agent (i.e. hydrogen sulphatesalt-form). The mixture of the two forms were dispersed in Vitamin ETPGS according to analogous methods to those described in Example 6 andfilled into HPMC capsules. The specific compositions of the comparatorformulations are shown in Table 5.

TABLE 5 Comparator compositions Agent, free base Agent (i.e. hydrogenform/mg sulphate salt)/mg (%Example w/w) (% w/w) Carrier Matrix (mg) C10.605 mg 29.645 mg Vitamin E TPGS (0.4% w/w) (19.76% w/w) (119.75 mg) C2 0.15 mg  30.09 mg Vitamin E TPGS (0.1% w/w) (20.06% w/w) (119.76 mg) C30.075 mg 30.165 mg Vitamin E TPGS (0.05% w/w) (20.11% w/w) (119.76 mg)C4  0.03 mg  30.21 mg Vitamin E TPGS (0.02% w/w) (20.14% w/w) (119.76mg)

The dissolution data for the comparator formulations (Table 6) show thatdissolution decreased as the amount of free base form of the Agent inthe composition increased. A 90% drop in dissolution at 60 minutes isobserved for a formulation containing 0.4% w/w free base form of theAgent. Furthermore, the presence of 0.02% w/w free base of the Agentcaused a 13% drop in dissolution at 60 minutes. The data generated byanalysing the free-base containing comparator formulations show that thepH 6.5 dissolution method provides a good indication of the level offree-base form of the Agent present within the compositions.

TABLE 6 Dissolution results for comparator compositions in pH 6.5dissolution media Dissolution at Formulation of 60 minutes (%) C1 10 C243 C3 78 C4 87

The dissolution results for the compositions described in Example 6 andalso for the formulation of Example 1.7 are shown in Table 7. Greaterthan 96% dissolution at 60 minutes is achieved for all of theformulations, indicating that the Agent is substantially present in it'shydrogen sulphate salt-form in these compositions.

TABLE 7 Dissolution results in pH 6.5 dissolution media Formulation ofDissolution at Dissolution at 60 Example 60 minutes (%) Formulation ofminutes (%) 1.7 99 6.8 101 6.1 98 6.9 101 6.2 98 6.10 100 6.3 96 6.11 986.4 97 6.12 99 6.5 102 6.13 99 6.6 100 6.14 97 6.7 101 6.15 97

1-20. (canceled)
 21. A pharmaceutical composition consisting essentiallyof: (i) from 15 to 25 parts of a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 75 to 85 parts ofd-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS);wherein both parts are by weight and the sum of the parts (i)+(ii)=100;and wherein the hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS,and the composition is semi-solid or solid at ambient temperature.
 22. Apharmaceutical composition according to claim 21, consisting essentiallyof: (i) from 18 to 22 parts of a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 78 to 82 parts of Vitamin ETPGS; wherein both parts are by weight and the sum of the parts(i)+(ii)=100; and wherein the hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS,and the composition is semi-solid or solid at ambient temperature.
 23. Apharmaceutical composition according to claim 22, consisting essentiallyof: (i) from 19 to 21 parts of a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 79 to 81 parts of Vitamin ETPGS; wherein both parts are by weight and the sum of the parts(i)+(ii)=100; and wherein the hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide is dispersed within the Vitamin E TPGS,and the composition is semi-solid or solid at ambient temperature. 24.The pharmaceutical composition according to claim 21, wherein thecomposition contains 30.25+/−2 mg of a hydrogen sulphate salt of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide.
 25. The pharmaceutical compositionaccording to claim 21, wherein the composition contains 12.1+/−2 mg of ahydrogen sulphate salt of6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide.
 26. An oral capsule filled with thepharmaceutical composition of claim
 21. 27. An oral capsule filled withthe pharmaceutical composition of claim
 24. 28. An oral capsule filledwith the pharmaceutical composition of claim
 25. 29. A process forstabilizing a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide against dissociation into its free baseform, the process comprising: dispersing a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide into a carrier matrix consistingessentially of Vitamin E TPGS, in order to obtain a homogenous mixtureof finely divided particles that are dispersed throughout the carriermatrix, thereby stabilizing the hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide.
 30. The process of claim 29, furthercomprising filling the homogenous mixture into a capsule.
 31. Theprocess of claim 29 wherein the homogenous mixture consists essentiallyof (i) from 15 to 25 parts of a hydrogen sulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 75 to 85 parts of Vitamin ETPGS; wherein both parts are by weight and the sum of the parts(i)+(ii)=100.
 32. The process of claim 31, wherein the homogenousmixture consists essentially of: (i) from 18 to 22 parts of a hydrogensulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 78 to 82 parts of Vitamin ETPGS; wherein both parts are by weight and the sum of the parts(i)+(ii)=100.
 33. The process of claim 32, wherein the homogenousmixture consists essentially of: (i) from 19 to 21 parts of a hydrogensulphate salt of6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethoxy)-amide; and (ii) from 79 to 81 parts of Vitamin ETPGS; wherein both parts are by weight and the sum of the parts(i)+(ii)=100.